The present invention, in some embodiments thereof, relates to therapy, and more particularly, but not exclusively, to compounds which inhibit pancreatic endoplasmic reticulum kinase (PERK) activity and which are usable in treating diseases associated with aggregation-prone proteins, such as Huntington's disease.
Protein aggregation is a biological phenomenon in which misfolded proteins form, either intracellularly or extracellularly, aggregates which are often toxic. Aggregation-prone proteins produce cellular stress, toxicity and death and are the cause of many of the neurodegenerative diseases, including, for example, ALS, Alzheimer's, Parkinson's and prion disease.
Proteins fold into their native conformation and undergo a series of post-translational modifications in the endoplasmic reticulum (ER) as part of the normal process of cellular homeostasis. Disruption of cellular protein folding results in ER stress. Cells respond to ER stress by activation of the unfolded protein response (UPR) pathways to survive the stress.
Pancreatic endoplasmic reticulum kinase (PERK), one of the three identified UPR transducers, is a kinase that phosphorylates a single known substrate eIF2a, leading to lower levels of translation initiation, which in turn globally reduces the load of newly synthesized proteins in the ER. Reduction in the overall protein-folding load is an effective response to reduce ER stress. In addition, PERK-mediated eIF2α phosphorylation also induces transcriptional activation to improve protein-folding capacity, thereby further promoting cell survival in stressed cells. Among the group of three prominent UPR transducers that includes also XBP1 and ATF6, PERK may have a broader range of cellular effects than other transducers, perhaps because of its unique role in regulating the general translation rate through the phosphorylation of eIF2α. Indeed, eIF2α phosphorylation appears to account for the entire range of the protective effects of PERK under ER stress. See, for example, Wang et al. [Chem Biol Drug Des 2010, 76: 480-495], and references cited therein.
Huntington's disease (HD) is a neurodegenerative disease, which initially affects medium spiny neurons in the brain striatum, and only later regions of the brain cortex. HD is a progressive, fatal genetic disorder affecting cognition and movement. HD is characterized by high sensitivity of striatal cells, the reasons of which are unknown, though mechanisms have been proposed involving proteins with enhanced expression in these cells. A hallmark of Huntington's disease is the pronounced sensitivity of striatal neurons to polyglutamine-expanded huntingtin expression.
HD arises from mutant forms of the huntingtin (Htt) protein with expanded polyglutamine (polyQ) tracts (>35 amino acids). This mutation causes Htt aggregation, which interferes with normal cell metabolism, leading to cytotoxicity. One of the effects of the expression of mutant Htt is the activation of the unfolded protein response (UPR) [Carnemolla et al., J Biol Chem 2009, 284: 18167-18173; Duennwald & Lindquist, Genes Dev 2008, 22: 3308-3319; Leitman et al., Nat Commun 2013, 4:2753; Reijonen et al., Exp Cell Res 2008, 314: 950-960].
Some of the present inventors have previously determined that in cells expressing mutant Huntington, the causative agent of Huntington's disease (HD), there is a strong induction of endoplasmic reticulum (ER) stress, especially in striatal cells, the cells that first degenerate in HD patients; and have showed that huntingtin toxicity was reduced by inhibiting PERK [Leitman et al., PLoS One 2014, 9(3):e90803; Leitman et al., Nat Commun 2013, 4:2753].
Small molecules inhibitors of PERK, designed mainly for treating cancer, but also in the context of neurodegenerative diseases such as prion disease, have been described, for example, in Wang et al. [Chem Biol Drug Des 2010, 76: 480-495]; Axten et al. [J Med Chem 2012, 55: 7193-7207]; Axten et al. [ACS Med Chem Lett 2013, 4:964-968]; Moreno et al. [Sci Transl Med 2013, 5(206):206ra138]; Radford et al. [Acta Neuropathol 2015, 130:633-642]; and International Patent Application Publications WO 2011/119663 and WO 2011/146748. These include, for example, the recently developed GSK2606414 and GSK2656157, and a molecule denoted A4, the structures of which are presented herein below.

GSK2606414 and GSK2656157 have been reported to be potent inhibitors of RIPK1, which renders their use as PERK inhibitors difficult to interpret [Rojas-Rivera et al., Cell Death Differ 2017, 24:1100-1110].
Additional background art includes Atkins et al. [Cancer Res 2013, 73:1993-2002]; Colla et al. [J Neurosci 2012, 32:3306-3320]; Costa-Mattioli et al. [Cell 2007, 129:195-206]; Das et al. [Science 2015, 348:239-242]; Efrat [Ann NY Acad Sci 1999, 875:286-293]; Guyenet et al. [J Vis Exp 2010, (39):1787]; Halliday et al. [Cell Death Dis 2015, 6:e1672]; Krishnamoorthy et al. [Cell Cycle 2014, 13:801-806]; Li et al. [NeuroRx 2005, 2:447-464]; Ma et al. [Nat Neurosci 2013, 16:1299-1305]; Mangiarini et al. [Cell 1996, 87:493-506]; Moreno et al. [Nature 2012, 485:507-511]; Sidrauski et al. [Elife 2013, 2:e00498]; Tsaytler et al. [Science 2011, 332:91-94]; Vieira et al. [PloS One 2015; 10(8):e0135570]; and U.S. Patent Application Publication No. 2009-0163545.